Folate-Appended Hydroxypropyl-β-Cyclodextrin Induces Autophagic Cell Death in Acute Myeloid Leukemia Cells

Acute myeloid leukemia (AML) is a heterogenous myeloid neoplasm that remains challenging to treat. Because intensive conventional chemotherapy reduces survival rates in elderly patients, drugs with lower toxicity and fewer side effects are needed urgently. 2-Hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) is used clinically as a pharmaceutical excipient for poorly water-soluble drugs. Previously, we showed that HP-beta-CyD exerts antitumor activity by disrupting cholesterol homeostasis. Recently, we developed folate-conjugated HP-beta-CyD (FA-HP-beta-CyD) and demonstrated its potential as a new antitumor agent that induces not only apoptosis, but also autophagic cell death; however, we do not know whether FA-HP-beta-CyD exerts these effects against AML. Here, we investigated the effects of FA-HP-beta-CyD on folate receptor (FR)-expressing AML cells. We found that the cytotoxic activity of FA-HP-beta-CyD against AML cells was stronger than that of HP-beta-CyD. Also, FA-HP-CyD induced the formation of autophagosomes in AML cell lines. FA-HP-beta-CyD increased the inhibitory effects of cytarabine and a BCL-2-selective inhibitor, Venetoclax, which are commonly used treat elderly AML patients. Notably, FA-HP-beta-CyD suppressed the proliferation of AML cells in BALB/c nude recombinase-activating gene-2 (Rag-2)/Janus kinase 3 (Jak3) double-deficient mice with AML. These results suggest that FA-HP-beta-CyD acts as a potent anticancer agent for AML chemotherapy by regulating autophagy.